Trial Outcomes & Findings for Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study (NCT NCT02805790)

Last Updated: 2020-07-17

Results Overview

Distance in meters walked on the 6-minute walk test (6MWT) at end of treatment, where end of treatment means end of week 4 for Period 1 and end of week 12 for Period 2.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

30 participants

Primary outcome timeframe

End of Week 4 and End of Week 12

Results posted on

2020-07-17

Participant Flow

Participant milestones

Participant milestones
Measure	Elamipretide, Then Placebo Participants first received 40 mg of elamipretide once daily subcutaneously for 4 weeks. After a washout period of 4 weeks, they then received placebo administered once daily subcutaneously for 4 weeks. Elamipretide: 40 mg elamipretide administered once daily subcutaneously	Placebo, Then Elamipretide Participants first received placebo once daily subcutaneously for 4 weeks. After a washout period of 4 weeks, they then received 40 mg of elamipretide once daily subcutaneously for 4 weeks. Placebo: 4 weeks of treatment with placebo administered once daily subcutaneously
First Intervention (4 Weeks) STARTED	14	16
First Intervention (4 Weeks) COMPLETED	14	16
First Intervention (4 Weeks) NOT COMPLETED	0	0
Washout (4 Weeks) STARTED	14	16
Washout (4 Weeks) COMPLETED	14	16
Washout (4 Weeks) NOT COMPLETED	0	0
Second Intervention (4 Weeks) STARTED	14	16
Second Intervention (4 Weeks) COMPLETED	14	15
Second Intervention (4 Weeks) NOT COMPLETED	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Elamipretide, Then Placebo Participants first received 40 mg of elamipretide once daily subcutaneously for 4 weeks. After a washout period of 4 weeks, they then received placebo administered once daily subcutaneously for 4 weeks. Elamipretide: 40 mg elamipretide administered once daily subcutaneously	Placebo, Then Elamipretide Participants first received placebo once daily subcutaneously for 4 weeks. After a washout period of 4 weeks, they then received 40 mg of elamipretide once daily subcutaneously for 4 weeks. Placebo: 4 weeks of treatment with placebo administered once daily subcutaneously
Second Intervention (4 Weeks) Physician Decision	0	1

Baseline Characteristics

Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Elamipretide, Then Placebo n=14 Participants Participants first received 40 mg of elamipretide once daily subcutaneously for 4 weeks. After a washout period of 4 weeks, they then received placebo administered once daily subcutaneously for 4 weeks.	Placebo, Then Elamipretide n=16 Participants Participants first received placebo once daily subcutaneously for 4 weeks. After a washout period of 4 weeks, they then received 40 mg of elamipretide once daily subcutaneously for 4 weeks.	Total n=30 Participants Total of all reporting groups
Age, Continuous	41.5 years STANDARD_DEVIATION 16.67 • n=5 Participants	48.6 years STANDARD_DEVIATION 9.68 • n=7 Participants	45.3 years STANDARD_DEVIATION 13.63 • n=5 Participants
Sex: Female, Male Female	10 Participants n=5 Participants	15 Participants n=7 Participants	25 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	13 Participants n=5 Participants	16 Participants n=7 Participants	29 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	14 participants n=5 Participants	16 participants n=7 Participants	30 participants n=5 Participants
Body Mass Index	22.8 kg/m^2 STANDARD_DEVIATION 5.19 • n=5 Participants	25.3 kg/m^2 STANDARD_DEVIATION 5.46 • n=7 Participants	24.1 kg/m^2 STANDARD_DEVIATION 5.39 • n=5 Participants

PRIMARY outcome

Timeframe: End of Week 4 and End of Week 12

Population: All participants for whom the distance walked on the 6MWT was measured.

Distance in meters walked on the 6-minute walk test (6MWT) at end of treatment, where end of treatment means end of week 4 for Period 1 and end of week 12 for Period 2.

Outcome measures

Outcome measures
Measure	Elamipretide n=29 Participants Participants who received 40mg Elamipretide administered once daily subcutaneously either the first or the last 4 weeks of the study.	Placebo n=30 Participants Participants who received Placebo administered once daily subcutaneously either the first or the last 4 weeks of the study.
Distance Walked on the 6-minute Walk Test (6MWT) by Visit	394.1 meters Standard Deviation 134.16	378.2 meters Standard Deviation 125.10

SECONDARY outcome

Timeframe: Last 7 days prior to the date of end of treatment visit

Population: All participants for whom wrist accelerometer counts by day was measured.

Wrist Accelerometer Counts by the last 7 days prior to the date of the end of treatment visit; End of treatment being end of Week 4 for Treatment Period 1 and end of Week 12 for Treatment Period 2. Subjects wore an activity monitor, or wrist accelerometer, on their wrist daily (from the Screening Visit to the End-of-Study/Early Discontinuation Visit). As a measure of physical activity and mobility, subjects wore an activity monitor, or wrist accelerometer, which measured mean vector magnitude of accelerations per daywith higher counts indicating a more active status. Raw acceleration data was converted into proprietary counts which was used to estimate physical activity. The data was transformed from 30 Hz data into 1 minute epoch data; this 1 minute epoch data were used for the analysis of as the vector magnitude of the wrist data.

Outcome measures

Outcome measures
Measure	Elamipretide n=30 Participants Participants who received 40mg Elamipretide administered once daily subcutaneously either the first or the last 4 weeks of the study.	Placebo n=29 Participants Participants who received Placebo administered once daily subcutaneously either the first or the last 4 weeks of the study.
Wrist Accelerometer Counts by Day	1329.4 counts by day Standard Deviation 505.28	1286.3 counts by day Standard Deviation 507.83

SECONDARY outcome

Timeframe: Last 7 days prior to the date of end of treatment visit

Population: All participants for whom hip accelerometer counts by day was measured.

Average Hip Accelerator Counts by last 7 days predose, and prior to end of treatment; End of treatment being Week 4 for Treatment Period 1 and Week 12 for Treatment Period 2. As a measure of physical activity and mobility, subjects wore an activity monitor, or hip accelerometer, on their hip (or belt line) daily during waking hours (minimum of at least 7 consecutive days immediately prior to study drug administration in each Treatment Period \[Predose; at Visit 2 for Treatment Period 1 and at Visit 4 for Treatment Period 2\]), and at the end of each Treatment Period \[at Visit 3 for Treatment Period 1 and Visit 5 for Treatment Period 2\]), which measured average acceleration per day, with higher counts indicating a more active status. Raw acceleration data was converted into proprietary counts which was used to estimate physical activity. The data was transformed from 30 Hz data into 1 minute epoch data; this 1 minute epoch data was used for the analysis of mean vertical axis (Y) cou

Outcome measures

Outcome measures
Measure	Elamipretide n=30 Participants Participants who received 40mg Elamipretide administered once daily subcutaneously either the first or the last 4 weeks of the study.	Placebo n=30 Participants Participants who received Placebo administered once daily subcutaneously either the first or the last 4 weeks of the study.
Average Hip Accelerator Counts by Day End of Treatment	150.6 counts by day Standard Deviation 162.13	148.1 counts by day Standard Deviation 115.04
Average Hip Accelerator Counts by Day Predose	384.2 counts by day Standard Deviation 130.70	380.6 counts by day Standard Deviation 126.43

SECONDARY outcome

Timeframe: End of Week 4 and End of Week 12

Population: All participants for whom Neuro-QoL Fatigue Short Form Score was measured.

Participants respond to the following statements of the Quality of Life in Neurological Disorders Fatigue Assessment (Neuro-QOL Fatigue Item Bank at end of treatment: I felt exhausted;I felt that I had no energy; I felt fatigued; I was too tired to do my household chores;I was too tired to leave the house;I was frustrated by being too tired to do the things I wanted to do; I felt tired; I had to limit my social activity because I was tired.Individual response options range from a score of 1 to 5, where 1=Never, 2=Rarely, 3=Sometimes, 4=Often, and 5=Always for end of treatment, where end of treatment period is end of week 4 for period 1, and end of week 12 for period 2. Raw scores are calculated as simple summed scores to an Item Response Theory Metric referred to as the T-score metric. Higher T-score means more fatigue, which means a worse outcome, with possible scores ranging from 29.5 to 74.1. Mean population T-score and standard deviation was reported.

Outcome measures

Outcome measures
Measure	Elamipretide n=29 Participants Participants who received 40mg Elamipretide administered once daily subcutaneously either the first or the last 4 weeks of the study.	Placebo n=30 Participants Participants who received Placebo administered once daily subcutaneously either the first or the last 4 weeks of the study.
Neuro-QoL Fatigue Short Form Score: Total T-Scores (Question 1-8)	50.9 T-score Standard Deviation 7.69	54.7 T-score Standard Deviation 10.35

SECONDARY outcome

Timeframe: Last 7 days of Week 4 and Last 7 days of Week 12

Population: All participants for whom PMMSA was measured at end of treatment.

Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) Total Fatigue score at end of treatment (sum of Q1 to Q4; tiredness/muscle weakness) is scored as follows: 1=Not at all, 2=Mild, 3=Moderate, and 4=Severe. Total score range is 4-16; lower score means less fatigue and better outcome, higher score means more fatigue and worse outcome. Participants rate the following: Tiredness at rest, Tiredness during activities, Muscle weakness at rest, Muscle weakness during activities, at the end of each treatment period, where end of treatment period is the weekly average of the last 7 days of week 4 for period 1 and the last 7 days of week 12 for period 2.

Outcome measures

Outcome measures
Measure	Elamipretide n=30 Participants Participants who received 40mg Elamipretide administered once daily subcutaneously either the first or the last 4 weeks of the study.	Placebo n=30 Participants Participants who received Placebo administered once daily subcutaneously either the first or the last 4 weeks of the study.
Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) Total Fatigue Score by Week	9.1 score on a scale Standard Deviation 2.35	10.7 score on a scale Standard Deviation 2.88

SECONDARY outcome

Timeframe: End of Week 4 and End of Week 12

Population: All participants for whom the 3TUG test was measured.

Participant performed 3TUG test after the 6MWT, and after at least 15 minutes rest prior to study drug administration in each Treatment Period (End of Week 4 for Period 1 and End of Week 12 for Period 2.) Participant was directed to stand up from chair, walk at normal pace to the line on the floor 3 meters away,turn, walk back to the chair at normal pace, sit down again; activity was timed, in seconds. Activity is repeated 3 times consecutively without rest and an average time is calculated.

Outcome measures

Outcome measures
Measure	Elamipretide n=29 Participants Participants who received 40mg Elamipretide administered once daily subcutaneously either the first or the last 4 weeks of the study.	Placebo n=30 Participants Participants who received Placebo administered once daily subcutaneously either the first or the last 4 weeks of the study.
Triple Timed Up and Go (3TUG) Test by Visit	35.3 seconds Standard Deviation 16.66	35.2 seconds Standard Deviation 15.79

SECONDARY outcome

Timeframe: End of Week 4 and End of Week 12

Population: All participants for whom the Patient Global Assessment was measured.

Patient-reported current health status at end of treatment, where end of treatment means End of Week 4 for Period 1 and End of Week 12 for Period 2. PGA Scale is as follows: 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 5=Poor. Higher score means worse health status, means worse outcome.

Outcome measures

Outcome measures
Measure	Elamipretide n=29 Participants Participants who received 40mg Elamipretide administered once daily subcutaneously either the first or the last 4 weeks of the study.	Placebo n=30 Participants Participants who received Placebo administered once daily subcutaneously either the first or the last 4 weeks of the study.
Patient Global Assessment [PGA] Score by Visit, Continuous	3.4 score on a scale Standard Deviation 0.91	3.7 score on a scale Standard Deviation 1.01

SECONDARY outcome

Timeframe: End of Week 4 and End of Week 12

Population: All participants for whom the Patient Global Assessment was measured.

Outcome measures

Outcome measures
Measure	Elamipretide n=29 Participants Participants who received 40mg Elamipretide administered once daily subcutaneously either the first or the last 4 weeks of the study.	Placebo n=30 Participants Participants who received Placebo administered once daily subcutaneously either the first or the last 4 weeks of the study.
Patient Global Assessment by Visit, Categorical Good	12 Participants	8 Participants
Patient Global Assessment by Visit, Categorical Fair	11 Participants	12 Participants
Patient Global Assessment by Visit, Categorical Poor	3 Participants	7 Participants
Patient Global Assessment by Visit, Categorical Excellent	1 Participants	1 Participants
Patient Global Assessment by Visit, Categorical Very Good	2 Participants	2 Participants

SECONDARY outcome

Timeframe: End of Week 4 and End of Week 12

Population: All participants for whom the Physician Global Assessment was measured.

Physician Global Assessment (PhGA) Physician-reported overall health status at end of treatment, where end of treatment means End of Week 4 for Period 1 and End of Week 12 for Period 2.: 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 5=Poor. Higher scores equal worse outcome.

Outcome measures

Outcome measures
Measure	Elamipretide n=29 Participants Participants who received 40mg Elamipretide administered once daily subcutaneously either the first or the last 4 weeks of the study.	Placebo n=30 Participants Participants who received Placebo administered once daily subcutaneously either the first or the last 4 weeks of the study.
Physician Global Assessment (PhGA) By Visit, Continuous	3.1 score on a scale Standard Deviation 0.80	3.3 score on a scale Standard Deviation 0.84

SECONDARY outcome

Timeframe: End of Week 4 and End of Week 12

Population: All participants for whom the Physician Global Assessment was measured.

Outcome measures

Outcome measures
Measure	Elamipretide n=29 Participants Participants who received 40mg Elamipretide administered once daily subcutaneously either the first or the last 4 weeks of the study.	Placebo n=30 Participants Participants who received Placebo administered once daily subcutaneously either the first or the last 4 weeks of the study.
Physician Global Assessment (PhGA) By Visit, Categorical Excellent	0 Participants	0 Participants
Physician Global Assessment (PhGA) By Visit, Categorical Very Good	6 Participants	5 Participants
Physician Global Assessment (PhGA) By Visit, Categorical Good	17 Participants	13 Participants
Physician Global Assessment (PhGA) By Visit, Categorical Fair	4 Participants	10 Participants
Physician Global Assessment (PhGA) By Visit, Categorical Poor	2 Participants	2 Participants

Adverse Events

Elamipretide

Serious events: 0 serious events

Other events: 30 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Rekha Sathyanarayana, Executive Director, Clinical Operations

Stealth BioTherapeutics Inc.

Phone: 617-762-2579

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Investigator may not submit for publication or presentation the results of this study without first receiving written authorization from Stealth BioTherapeutics Inc. Stealth BioTherapeutics Inc., agrees that before it publishes any results of the study, it shall provide the Investigator with at least 30 days for review of the pre-publication manuscript prior to the submission of the manuscript to the publisher.
Publication restrictions are in place

Restriction type: OTHER

Measure	Elamipretide n=30 participants at risk Participants received 40 mg of elamipretide once daily subcutaneously for 4 weeks, either in the first 4 weeks of treatment, or in the last 4 weeks of treatment.	Placebo n=30 participants at risk Participants received placebo once daily subcutaneously for 4 weeks, either in the first 4 weeks of treatment or the last 4 weeks of treatment.
General disorders Injection site erythema	56.7% 17/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.	3.3% 1/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.
General disorders Injection site pruritus	46.7% 14/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.	0.00% 0/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.
General disorders Injection site pain	20.0% 6/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.	3.3% 1/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.
General disorders Injection site urticaria	20.0% 6/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.	0.00% 0/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.
General disorders Injection site bruising	6.7% 2/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.	6.7% 2/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.
General disorders Injection site irritation	10.0% 3/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.	3.3% 1/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.
Infections and infestations Urinary Tract Infection	6.7% 2/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.	0.00% 0/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.
Infections and infestations Viral Upper Respiratory Tract Infection	6.7% 2/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.	0.00% 0/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.
Gastrointestinal disorders Abdominal Pain	6.7% 2/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.	3.3% 1/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.
Gastrointestinal disorders Diarrhoea	3.3% 1/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.	6.7% 2/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.
Musculoskeletal and connective tissue disorders Muscle Spasms	3.3% 1/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.	6.7% 2/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.	6.7% 2/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.
Nervous system disorders Dizziness	10.0% 3/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.	3.3% 1/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.
Nervous system disorders Dysarthria	6.7% 2/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.	0.00% 0/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.
Nervous system disorders Headache	0.00% 0/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.	6.7% 2/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.
Injury, poisoning and procedural complications Fall	3.3% 1/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.	10.0% 3/30 • Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.